Commentary: Toward Greater Integration and Specificity in Conceptual Models of Neurocognitive Functioning in Childhood Cancer Survivors
1 City of Hope National Medical Center and Beckman Research Institute, Duarte, California, and 2 Children’s Hospital and Clinics, St. Paul, Minnesota
All correspondence should be sent to Sunita Patel, Director, Behavioral Research in Pediatrics, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, California 91010–3000. E-mail: supatel{at}coh.org.
Psychologists have played a significant role in identifying and facilitating understanding of neurocognitive outcomes in children and adolescents surviving cancer. Moore (this issue) provides an excellent overview of the salient medical and demographic predictors of adverse neurocognitive impact, while Butler and Mulhern (this issue) describe promising findings from recent pioneering studies aimed at treating cognitive and neurobehavioral side effects. Moore’s discussion of past research gains is notable for its integration of a neuropathological perspective with select findings from animal model studies. Butler and Mulhern’s discussion is similarly exceptional for integration of perspectives not commonly elaborated upon in articles on the neurocognitive functioning of childhood cancer survivors. Specifically, they discuss the potential importance of a "psychotherapeutic" component, along with "family environment" and school-based "ecological interventions" in cognitive remediation intervention programs. This expansive rehabilitation model, when viewed with Moore’s discussion of neurobiological underpinnings, reflects a movement toward greater conceptual integration. This is a trend that we, as early career investigators, hope will increasingly materialize as psychologists continue to study neurocognitive issues in childhood cancer survivors. There are several areas in which we anticipate research to evolve in the next decade.
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Identification of Risk and Resilience Factors |
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Research from the past two decades has led to a clearer understanding of medical and treatment factors that place survivors at differential risks for adverse learning and neurobehavioral outcomes (Ris & Noll, 1994
). This line of inquiry is expected to continue as we strive to isolate and understand relative, as well as synergistic, contributions of various treatment elements. For example, only recently have the neurocognitive contributions of surgical resection been systematically evaluated prior to radiation or chemotherapy in pediatric brain tumor patients (Carpentieri et al., 2003). While we have made progress in identifying some of the particular chemotherapies that impact cognitive and behavioral status, further specificity is warranted: Do high-dose systematic chemotherapies have a more deleterious effect on very young children than is commonly seen in older children, since the blood-brain barrier is more permeable in infants? Is there a threshold dose at which high-dose systematic or intrathecal methotrexate places different groups of children at risk for cognitive compromise (i.e., those under age 6 relative to older children)?
There remain many questions about the potential neurotoxicities of agents used in prophylactic as well as ablative conditioning regimens, and we anticipate continued work in this area. For example, the potential risk factor of corticosteroids, particularly when combined with specific chemotherapeutic agents, is likely to become increasingly clarified in the near future (Waber et al., 2000). In the coming decade, we also anticipate more in-depth inquiry into previously identified, long-established risk factors from new perspectives using novel and multidisciplinary research strategies. One such recent effort has led us to a more refined understanding of the neuropathology and neural substrates underlying cognitive impairments in children radiated at a young age (Mulhern et al., 2001). There remain many variables, including gender, that have been previously associated with elevated risk but without clear understanding of the underlying mechanisms. We need additional inquiry into why gender is a risk factor; to what extent differential brain development, hormonal influences, and socialization practices contribute to girls’ increased risk; and whether the gender risk "valence" varies with other predictors such as age at treatment and time interval.
We also need greater precision in the constellation of risk factors for different patient subgroups based on demographic as well as medical characteristics. Preliminary efforts examining socioeconomic influences suggest an interactive effect of socioeconomic status in longitudinal intellectual outcomes. Intellectual outcomes are expected to continue (Patel, Herrera, Katz, & Turk, manuscript in preparation). A goal of such future research should be to investigate whether any specific belief systems, knowledge, financial resources, stressors, or behavioral practices of families of cancer survivors play a role as moderating, or even protective, factors in long-term neurocognitive outcomes. A minor conceptual shift during the process of discerning risk factors may highlight additional moderating or mediating variables to investigate. For example, family variables have been shown to add significantly, beyond medical variables, to the prediction of cognitive outcomes in children with brain tumors (Carlson-Green, Morris, & Krawiecki 1995); given this finding, it is reasonable to ask about what family factors may serve to improve outcomes. While family factors and parent behaviors are unlikely to prevent actual cognitive impact (particularly when treatments involve high-dose cranial radiation at a young age), there may be "windows of opportunity" to positively influence outcomes (Patel, Baumeister, Katz, Wagener, & Buckwater, manuscript submitted). Our ability to identify and understand any substantial demographic and behavioral resilience factors relevant to cognitive and academic outcomes will be greatly enhanced by integrating social, emotional, and behavioral aspects into our conceptual model of neurocognitive functioning in childhood cancer survivors.
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Evaluation of Modern Protocols to Limit Toxicity |
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TopIdentification of Risk and...Evaluation of Modern Protocols...Treating Adverse OutcomesAvailability and Accessibility...Future TrendsReferences |
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Behind most research efforts to delineate risk factors for adverse outcomes is the inherent hope that once known, such risk factors can be avoided or limited without impacting survival rates. Greater specificity in the relative and interactive contributions of risk factors by subgroup should help the medical team better evaluate and stratify cancer treatment protocols. An important focus of past studies has attempted to prevent or limit toxicity by reducing, delaying, or eliminating cranial radiation and specific chemotherapies from cancer treatment protocols (Moore, this issue). We anticipate that psychologists will continue to help evaluate the functional impact of modified cancer treatment protocols. It has become increasingly clear that radiation is likely to remain the cornerstone of treatment for malignant brain tumors to maintain current survival rates (Thomas et al., 2000
). Subsequently, new radiation technologies such as three-dimensional conformal and intensity-modulated radiation therapies are increasingly used to minimize radiation dose to normal brain tissue (Lin et al., 2000). However, even when radiation is very focused, its impact on brain systems may be found in distant locations (Waldrop, Davis, Padgett, Shapiro, & Morris, 1998). As cancer centers upgrade their radiation technology, it will be important to evaluate which technology for what types of brain tumors actually results in substantially reduced adverse neurocognitive side effects, along with the anticipated benefit for auditory and endocrine functions. |
Treating Adverse Outcomes |
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TopIdentification of Risk and...Evaluation of Modern Protocols...Treating Adverse OutcomesAvailability and Accessibility...Future TrendsReferences |
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Until recently, research has focused far more on describing the nature and extent of adverse neurocognitive impacts, with little scientific attention directed toward treatment of those outcomes. Fortunately, recent investigations from multisite psychology consortia using rigorous methodology have applied pharmacological and multimodal cognitive rehabilitation techniques to treat long-term attention and executive deficits with promising results (Butler & Mulhern, this issue). Given the associations of school and family factors in predicting cognitive and academic outcomes in this patient population (Carlson-Green et al., 1995
; Leigh & Miles, 2002), future cognitive intervention studies are expected to more broadly incorporate the multiple systems that are part of the survivor’s daily life. Greater integration of such ecological influences as parents, teachers, peers, mentors, and community resources may be particularly relevant to further improve and generalize treatment efficacy, as well as deliver evidence-based interventions in a practical and cost-effective manner. Such considerations are particularly relevant for families served by rural cancer centers, where access to clinic-based remediation programs and expertise is limited. Future intervention studies will need to incorporate tools and strategies, such as Web-based interactive programs, to improve accessibility for these families. Clinical intervention studies to treat chronic effects of treatment are still in their infancy and likely to continue into the next decade. With continued progress in this area, we will need to evaluate the benefits of earlier, perhaps prophylactic, behavioral and pharmacological interventions and determine whether such efforts minimize progressive decline. The greater our refinement and specificity of the neuropsychological components and learning processes adversely impacted by medical treatments, the better we can tailor our treatment interventions. Similarly, advances in our understanding of the neurobiological substrates of cancer-related cognitive impairments should inform and fine-tune our behavioral and pharmacological interventions. We anticipate eventual integration of functional imaging techniques into cognitive rehabilitation programs to evaluate the efficacy of tailored strategies directed at mitigating underlying neuropathology for the individual survivor. Embracing a truly biopsychosocial model of children’s outcomes should be particularly fruitful in developing innovative treatment approaches.
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Availability and Accessibility of Resources |
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TopIdentification of Risk and...Evaluation of Modern Protocols...Treating Adverse OutcomesAvailability and Accessibility...Future TrendsReferences |
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An important consideration for future research efforts and the ways in which new knowledge can translate into clinical psychological service is the issue of availability and accessibility of resources. Many pediatric cancer centers do not have access to neuropsychologists to conduct comprehensive assessments or interventions, for either research or clinical care purposes. Even when neuropsychological resources are available, different sites (or even different neuropsychologists at the same site) may use different test batteries for their assessment. This contributes to the difficulty in comparing outcomes of children with the same type of cancer treated at different sites and limits the generalizability of results. To address this significant problem, the Psychology Discipline Committee of the Children’s Oncology Group (COG) has recently formulated a relatively brief neurocognitive and quality of life battery recommended for standard use in COG research protocols (D. Armstrong, personal communication, April 1, 2004). Details of the recommended test battery, along with other relevant communications, eventually will be available on the COG website under the soon-to-be-established psychology discipline section (D. Armstrong, personal communication, April 1, 2004). This raises the issue of access to knowledge about new research efforts or developing trends in progress, as many psychologists who work in pediatric oncology settings may not know where to seek such information or have no access to the information if they are not part of the COG membership. This can be remedied somewhat by encouraging researchers and the leaders in our field to distribute new information and research findings across multiple forums and media, including pediatric psychology conferences, COG meetings, conferences of the American Psychological Association, and articles in journals geared toward a broader audience.
Another commonly cited obstacle to neurocognitive research is that even when there is a neuropsychologist or trained pediatric psychologist available, there is insufficient funding and/or time to conduct labor-intensive neurocognitive evaluations. One proposal to address this problem is the COG Nursing Discipline Committee’s recent initiative to obtain funding for the purpose of training nurses to administer quality of life and basic neurocognitive tests to patients enrolled in research studies. Other efforts to address the problem include the recent substantial increase in reimbursement from COG for neurocognitive testing as part of cancer treatment protocols. Additionally, funded principal investigators are encouraged to purchase and ship specific (and sometimes expensive) neuropsychological instruments to sites assisting with data collection.
Clearly, creative efforts are being implemented to address some of the obstacles that have previously resulted in poor data collection rates for multisite cancer protocol studies. While this is encouraging, more attention also needs to be directed at helping patients and their families better access what may be available at their local cancer center and nationally. The issue of availability and accessibility for families in rural, nonmetropolitan communities requires continued attention and creative solutions. If ignored, the results of our outcome studies may be limited to those children and their families who are able to travel to research sites, can afford or have insurance coverage for neuropsychological testing, have access to computers and community resources, and are able to successfully advocate for support in their local school districts.
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Future Trends |
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TopIdentification of Risk and...Evaluation of Modern Protocols...Treating Adverse OutcomesAvailability and Accessibility...Future TrendsReferences |
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To summarize, we envision that the next decade will bring increased appreciation for a more integrated, yet more precise, biopsychosocial understanding of neurocognitive outcomes and treatment approaches. There are a number of challenges that continue to require attention as psychologists advance research in this area. Research in pediatric cancer is impeded by limitations in statistical power due to the low incidence of some cancers, along with problems with design and statistical methodology (e.g., lack of adequate control groups, limited longitudinal studies). The obstacles are further exacerbated by changes in treatment protocols over time (e.g., types of chemotherapies given, order of treatments, amount of dosing). The later results in research outcomes that may no longer be applicable, as the treatments have changed or do not apply to children who were not treated with the same protocol. Some of these issues can continue to be improved with greater collaborative efforts. Specifically, collaboration among larger work groups, such as multisite consortia and the COG member institution centers, will allow for larger sample sizes and increased methodological sophistication to prospectively address complex questions. Participation in COG also facilitates contributions from neurocognitive researchers who may otherwise not have access to the same resources as do psychologists based in large or well-funded comprehensive cancer centers. Additionally, continued multidisciplinary collaboration, particularly between psychologists and pediatric oncologists, will improve surveillance and result in a feedback loop that minimizes deleterious outcomes of medical treatments. We enthusiastically anticipate that psychologists and neuropsychologists in the coming decade will continue to significantly influence and improve the care and quality of life of childhood cancer survivors.
Received March 2, 2004; revision received May 12, 2004; accepted June 8, 2004
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References |
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TopIdentification of Risk and...Evaluation of Modern Protocols...Treating Adverse OutcomesAvailability and Accessibility...Future TrendsReferences |
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Carlson-Green, B., Morris, R. D., & Krawiecki, N. (1995). Family predictors of outcome in pediatric brain tumors. Journal of Pediatric Psychology, 20, 769–784.
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